ABSTRACT ? Immunologic and virologic determinants of congenital cytomegalovirus transmission and disease in rhesus monkeys. Congenital cytomegalovirus (CMV) is the leading infectious cause of birth defects and infant neurologic deficits, yet gaps in our knowledge of the protective maternal immune responses has impeded the development of a successful CMV vaccine to eliminate this cause of infant morbidity. The overarching goal of this Program is to end the stalemate in congenital CMV vaccine research by defining the key immune responses and viral-host interactions that dictate primary fetal CMV transmission and disease. To accomplish this, the Program builds on our novel nonhuman primate (NHP) model of placental transmission of rhesus CMV (RhCMV). Specifically, the Program will employ this newly defined NHP model in RhCMV-seronegative pregnant dams to investigate the immune correlates of placental virus transmission and fetal disease (Project 1) and the viral determinants of placental RhCMV transmission (Project 2). An Administrative Core and four scientific Cores provide critical expertise and resources required to integrate Program activities, including administrative infrastructure and oversight (Administrative Core), NHP study implementation expertise (Core 1), virus production and quantitation (Core 2), whole viral genome sequencing and population genetics (Core 3) and statistical analyses and mathematical modeling (Core 4). Our overall hypothesis is that maternal humoral and cellular immunity provides partial protection against placental CMV transmission and disease, and viral-host immune interactions determine the emergence of both placentally transmitted and fetal CMV variants. Our overall specific aims are: 1) Demonstrate whether CMV-specific humoral and/or cellular responses confer protective efficacy against congenital infection and fetal disease; and 2) Define the key virologic determinants and viral selection pressures of placental CMV transmission and subsequent fetal disease. We expect the work of this Program will identify immune responses and virologic-host interactions that will guide the design of the next generation of congenital CMV vaccines and will also refine the NHP model to tailor it for future CMV vaccine candidate testing.